Cerebral cholinergic nerve system plays an important role in memory function. Degeneration of this nerve system is thought to be implicated in memory impairment seen in dementing disorders such as Alzheimeer's disease. The AchE activity has been found to be reduced in accordance with the decreased cholinergic function in the brain. The determination of cerebral regional AchE activity may, therefore, contribute greatly to clinical diagnosis, therapeutic evaluation and pathological elucidation of dementing and/or age-related neurological disorders.
Conventionally, AchE activity in the brain has been determined enzymatically or histochemically using homogenate or sections of postmortem brain tissue. Lipophilic acetylcholine analogs labeled with radionuclide have also been used to determine AchE activity in the brain by using autoradiagraphy or emission tomography (Japanese Patent Application laid-open No. 327497/1994). The emission tomographic method allows non-invasive determination of AchE activity in the living brain in both human and animal subjects. This method has been found to be of merit for clinical diagnosis or development of therapeutic drugs for degenerative disorders of cholinergic nerve system including Alzheimer's disease (Namba et. el., Brain Res., 667:278-282, 1994, Irie et. al., J. Nucl. Med., 37:649-655, 1996).
The radiolabeled compounds used in the method described in above publications must have following characteristics:
(1) Highly lipophilic to pass through the blood-brain barrier easily;
(2) Being specifically hydrolyzed by AchE in the brain;
(3) Being hydrolyzed to less lipophilic alcohol that is trapped in the brain; and
(4) Negligible cerebral incorporation of the hydrolyzed alcohol formed outside the brain.
The above application have shown the following radiolabeled compounds satisfying the above requirements; N-methylpiperidinyl-3-acetate, N-methylpiperidinyl-3-propionate, N-methylpiperidinyl-4-acetate and N-methylpiperidinyl-4-propionate, each of which has N-methyl group labeled with .sup.14 C. By using these compounds, autoradiographic determination of cerebral AchE activity ahs been achieved in rats. Furthermore, positron emission tomography (PET) using the .sup.11 C labeled compound has been done for non-invasive determination of cerebral AchE activity in living subjects (Iyo el. Al., Lancet, 349:1805-1809, 1997)
The conventional lipophilic acetylcholine analogs including the compounds described above, however, allow only .sup.11 C-labeling to give practically available radiolabeled compounds used for non-invasive determination of cerebral AchE activity. Therefore, PET using positron camera is the only selection allowed to be used for clinical application to human subjects. Because of the short half-life of .sup.11 C (about 20 min), PET scanning is restricted to performing in a facility with a cyclotron for radioisotope production. Meanwhile, single photon emission computed tomography (SPECT) using gamma camera is widely used for clinical practice, so the development of a radiolabeled compound applicable to SPECT has been demanded.